Contents

NMDA receptor antagonists induce a state called dissociative anesthesia, which is marked by catalepsy, amnesia, and analgesia.[1] Ketamine and other NMDA receptor antagonists are most frequently used in conjunction with diazepam as anesthesia in cosmetic or reconstructive plastic surgery[2] and in the treatment of burn victims.[3] Ketamine is a favored anesthetic for emergency patients with unknown medical history because it depresses breathing and circulation less than other anesthetics.[4] The NMDA receptor antagonist dextromethorphan is one of the most commonly used cough suppressants in the world.[5]

Because of these psychotomimetic effects, NMDA receptor antagonists, especially phencyclidine, ketamine, and dextromethorphan, are used as recreational drugs. At subanesthetic doses, these drugs have mild stimulant effects, and at higher doses, begin inducing dissociation and hallucinations.[15]

Most NMDA receptor antagonists are metabolized in the liver.[16][17] Frequent administration of most NMDA receptor antagonists can lead to tolerance, whereby the liver will more quickly eliminate NMDA receptor antagonists from the bloodstream.[18]

Exposure to NMDA receptor antagonists may cause a serious brain damage in the cingulate cortex and retrosplenial cortex regions of the brain. The experimental NMDA receptor antagonist MK-801 has been shown to cause neural vacuolization in test rodents that later develop into irreversible lesions called "Olney's Lesions."[19][20] Many drugs have been found that lessen the risk of neurotoxicity from NMDA receptor antagonists. Centrally acting alpha 2 agonists such as clonidine and guanfacine are thought to most specifically target the etiology of NMDA neurotoxicity. Other drugs acting on various neurotransmitter systems known to inhibit NMDA antagonist neurotoxicity include: anticholinergics, diazepam, barbiturates,[21]ethanol,[22] 5-HT2Aserotonin agonists,[23] and muscimol.[24]

Since NMDA receptors are one of the most harmful factors in excitotoxicity, antagonists of the receptors have held much promise for the treatment of conditions that involve excitotoxicity, including traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. This is counterbalanced by the risk of developing Olney's lesions, [25] although there is evidence against Olney's lesions forming in humans, and studies have started to find agents that prevent this neurotoxicity.[24][22] Most clinical trials involving NMDA receptor antagonists have failed due to unwanted side effects of the drugs; since the receptors also play an important role in normal glutamatergic function, blocking them has harmful effects.[26] This interference with normal function could be responsible for neuronal death that sometimes results from NMDA receptor antagonist use.[27]

The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, an NMDA receptor must bind to glutamate and to glycine. An NMDA receptor that is bound to glycine and glutamate and has an open ion channel is called "activated."

Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories: Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists, which block the ion channel by binding to a site within it.[12]

Memantine (Axura, Akatinol, Namenda, Ebixa, 1-amino-3,5-dimethylada-mantane) – moderate affinity, voltage-dependent uncompetitive antagonist.[37] Approved in the U.S. by the Food and Drug Administration for the treatment of Alzheimer's disease.[38]

↑Khan MJ, Seidman MD, Quirk WS, Shivapuja BG (2000). Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery257 (4): 177–81.